1. Field of the Invention
The present invention relates generally to the fields of medicine, pathology and molecular biology. More particularly, it concerns the involvement of miR function in the regulation of osteoclasts and osteoblasts. Specifically, the invention relates to the use of miR-34a for treating bone loss.
2. Description of Related Art
Osteoclast-mediated bone resorption plays an essential role in the dynamic bone remodeling in concert with osteoblast-mediated bone formation. Osteoclasts are derived from hematopoietic progenitors (Ash et al., 1980) in the monocyte/macrophage lineage (Scheven et al., 1986; Tondravi et al., 1997), and differentiate in response to the cytokine Receptor Activator of NFκB Ligand (RANKL) (Lacey et al., 1998; Yasuda et al., 1998); whereas osteoblasts are of mesenchymal lineage (Pittenger et al., 1999). Skeletal homeostasis in normal physiology is maintained by the tight coupling of bone resorption and bone formation (Edwards and Mundy, 2008). However, pathological increases in osteoclast function can cause several bone diseases such as osteoporosis (Novack and Teitelbaum, 2008). It is estimated that an osteoporotic fracture occurs every 3 seconds worldwide, many of which leads to life-threatening events especially in the elderly. With the increased prevalence and life-time risk, osteoporosis takes a huge personal and economic toll.
Excessive osteoclasts also promote bone metastasis, a frequent, debilitating and essentially incurable cancer complication that accounts for substantial morbidity and mortality in cancer patients. A bevy of tumors exhibit a strong tendency to metastasize to the bone, including breast, prostate, lung, skin, colon, stomach, bladder, uterus, rectum, thyroid and kidney cancers (Coleman, 1997). In bone metastasis, there is a vicious cycle in the osseous microenvironment, whereby bi-directional interactions between tumor cells and osteoclasts lead to both bone loss and tumor growth (Chirgwin and Guise, 2000; Ell and Kang, 2012). Osteoclast inhibitors, such as bisphosphonates and RANKL neutralizing antibody (denosumab), can interrupt this vicious cycle, thus reducing bone lesions, tumor burden, bone pain and mortality (Coleman, 2012; Mundy, 2002; Roodman, 2004). However, these drugs exhibit limitations such as moderate efficacy or high cost, as well as side effects including osteonecrosis of the jaw and renal toxicity (Brown and Coleman, 2012; Coleman, 2012; Khosla et al., 2007). Therefore, identification of novel suppressors of osteoclastogenesis will not only enhance the fundamental understanding of skeletal physiology but also facilitate the development of better therapies to prevent and treat multiple bone and cancer diseases.
MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development and physiology, as well as diseases such as cancer. They are small molecules that inhibit the stability and translation of multiple target messenger RNAs (mRNA). Recent studies have identified specific miRNAs as tumor suppressors or oncogenes for which loss- or gain-of-function contributes to malignancy (Chivukula and Mendell, 2008; Kato and Slack, 2008; Ventura and Jacks, 2009). Importantly, latest development of miRNA-based interventions such as miRNA mimetics or antagomirs in combination with novel nanoparticle, atelocollagen or lipid-mediated miRNA delivery systems has highlighted their tremendous therapeutic potential (Kasinski and Slack, 2011; Osaki et al., 2011; Pramanik et al., 2011; Takeshita et al., 2010; Trang et al., 2011). Nonetheless, how miRNAs regulate osteoclastogenesis, bone resorption and the bone metastatic niche is a provocative question that is still underexplored.